Hyperthermia induced brain oedema: Current status & future ...

Hyperthermia induced brain oedema: Current status & futureperspectives

Hari Shanker Sharma

Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anaesthesiology &Intensive Care Medicine, University Hospital, Uppsala University, S-751 85 Uppsala, Sweden

Received July 12, 2005

Recent years have witnessed a large number of deaths due to hyperthermia and heat-related illnessesacross the globe in human population resulting in great social and medical problems. The detailedmechanisms and probable therapeutic measures have still not been worked out. Sporadic autopsyreports show profound brain swelling leading to compression of vital centers that could beresponsible for instant death. Increased permeability of the blood-brain barrier (BBB) and brainswelling is also seen in experimental models of heat stress. It appears that hyperthermia isinstrumental in opening of the BBB either directly or indirectly leading to vasogenic oedemaformation, a feature crucial to molecular and cellular alteration in the brain inducing cell andtissue injury. The probable mechanisms and functional significance of heat induced brain oedemaand BBB damage in relation to neurodegenerative changes are discussed.

Key words Animal models - blood-brain barrier - brain oedema formation - cell and tissue injury - heat stress -human cases - neurochemicals - therapeutic measures

Brain oedema is a life-threatening complicationfollowing several kinds of central nervous system(CNS) injuries either caused by traumatic, ischaemic,metabolic or hypoxic insults1-4. A progressive brainoedema compresses the brain and increasesintracranial pressure resulting in tissuesoftening1,5-7. Excessive brain swelling in the craniumleads to instant death probably due to compressionand cellular damage of vital centers8-11.

Brain oedema caused by traumatic or ischaemicinjuries is well known2,11-16. However, oedemaformation following hyperthermic insults to the brain

is a new subject that is not emphasized either inclinical or experimental conditions. Our group wasthe first to report that hyperthermia caused by heatexposure is associated with breakdown of the blood-brain barrier (BBB)17-20 followed by profound brainswelling10,21.

It appears that development of brain oedemafollowing heat-related illnesses is an important factorassociated with brain damage causing long-termdisability and death in humans. Thus, an increasedunderstanding of progression, persistence andresolution of brain oedema induced by heat stress is

Indian J Med Res 123, May 2006, pp 629-652

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urgently needed to explore suitable therapeuticmeasures to minimize human suffering across theglobe.

Progressive brain oedema is life threatening

Brain oedema is defined as an increase in watercontent of the CNS following regional or globalinsult22,23. The early clinical symptoms of brainoedema includes headache, nausea, vomiting,disturbances of consciousness, and occasionallycoma2,3,24.

The oedema fluid spreads rapidly in bothlongitudinal and transverse directions from the siteof injury depending on the magnitude and severityof the primary insult1. This leads to whole brainswelling within 24 to 72 h in clinical conditions1,9,25.Raised intracranial pressure, papilledema, followedby herniation of brain and vascular infarction arepotential life threatening complications of brainoedema and are common causes of death26,27.

Types of brain oedema: About 39 yr ago, Klatzo(1967)23 classified brain oedema into vasogenic andcytotoxic types depending on their origin22,23.Vasogenic brain oedema occurs due to damage ofcerebral vessels allowing leakage of plasma proteinsand water into the brain extracellular environment.On the other hand, cytotoxic oedema is due toalterations in cell metabolism leading to wateraccumulation inside the cells9,28. Originally, cytotoxicoedema meant swelling of glial cells or astrocytes26.However, recent observations suggest that wateraccumulation can occur in all types of brain cells,e.g., the neurons, the glial cells and the vascularendothelial cells11,26. A considerable overlap existsbetween these two types of brain oedema in severalnoxious insults to the CNS, e.g., ischaemia, hypoxiaand trauma1,3,28,29.

Mechanisms of brain oedema formation: Increasedaccumulation of water either in the extracellular spaceof the brain or within the intracellular compartmentsof the cells may result due to osmotic imbalancebetween plasma and brain leading to osmotic oedemathat interferes with brain metabolism resulting inmetabolic oedema26. Inhibition of brain metabolism

by pharmacological agents, freezing lesion of the brainor ischaemia results in cell swelling and inducesmetabolic oedema30. Cyanide poisoning inducesoedema in the gray and white matter by inhibitingoxidative enzymes and a reduction in the cerebralblood flow26,31,32. Axonal swelling and myelinvesiculation are the prominent features of white matteroedema32. However, the BBB permeability to trypanblue or 131I-albumin remained intact33.

Trauma to the brain or cerebral microvesselsresults in the development of traumatic oedema33. TheBBB remains largely intact in osmotic and metabolicoedema, whereas leakage of plasma proteinscorrelates well with the development of traumaticbrain oedema25. Leakage of proteins at the cerebralcapillaries initiates complex processes in the brainfluid microenvironment resulting in a progressive andirreversible pathological and metabolic changes1,24.The vasogenic factors predominates in traumaticoedema in which cytotoxic factors contribute todamage of cell membranes and cell metabolism22.

Factors influencing brain oedema: Since the braindoes not contain lymphatic system to remove excesswater5, the accumulated oedema fluid percolatesthrough the cerebral compartment to reach CSF forits subsequent removal5. Thus, the hydrostatic andosmotic pressure differences between the vascular andcerebral compartments largely determine the filtrationand accumulation of water across the capillary wall34.

The cerebral capillaries are impermeable toproteins, electrolytes and water soluble nonelectrolytes6. The protein osmotic pressure in brainis almost zero because CSF protein is negligible5,26,28.Thus, the water permeability in brain is dependenton capillary hydrostatic pressure and protein osmoticpressure26,35. Oedema develops when proteinaccumulates in the brain resulting in the increase ofthe brain volume36. The biomechanics of brainoedema is thus influenced by several other biologicalfactors (Table I). However, the exact relationshipbetween capillary filtration, the driving force of waterdue to osmotic or hydrostatic gradients, hydraulicconductivity and tissue compliance under variouspathological conditions and their influence on brainoedema formation is still unknown2,26.

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Several endogenous neurochemical mediatorsknown to influence BBB function play importantroles in brain oedema formation37,38 (Table II).Neurochemicals may influence water transportfrom the vascular to the cerebral compartment

involving specific receptors and ion channels.Recent ly , the ro le of acquapr in-4 in waterpermeability across cerebral microvessels hasbeen suggested4 which requi res fur therinvestigation.

SHARMA: BRAIN OEDEMA IN HEAT STRESS 631

Table I. Physical factors influencing biomechanics of brain oedema formation

Factors Effect Brain oedema Mechanisms

Plasma osmotic pressure reduction in swelling altered

osmolality osmotic gradient

chronic hypotonicity normal loss of K+, other salts

brain volume

Tissue osmotic pressure accumulation of swelling increased capillary

tissue proteins, lactate, infiltration

products of cell cytolysis

Capillary permeability disturbances in swelling increased hydraulic

autoregulation of CBF, conductivity, altered

leakage of plasma osmotic gradient,

proteins increased capillary

infiltration

Capillary hydrostatic pressure defective autoregulation swelling hypertension

of CBF, breakdown of the

BBB permeability

Tissue hydrostatic pressure increased counter- interstitial pressure

balance altered oedema

Tissue complience higher in white matter swelling less glycoprotein,

low in gray matter swelling high glycoprotein

for cell adhesion

CBF, Cerebral blood flow; BBB, blood-brain barrier; [Compiled after Rapoport (1976). Data modified after Sharma et al., 1998]

Source of information - Refs 26, 11

Table II. Neurochemical mediators of brain oedema formation

Neurchemicals Thermoragulation BBB permeability Brain oedema

Serotonina ++ ++ ++

Prostaglandinsa +++ +++ +++

Arachidoinc acid ++ +++ +++

Bradykinina + ++ ++

Histaminea +/- +++ ++

Leukotrienes - + +

opioidsa + +/- +/-

Catecholamines +++ ++ ++

Free radicals - ++ ++

Nitric oxidea +/- + +/-

Compiled from various sources; +/-, further research are needed; +, involved; ++, well known; +++, established; -, not known;a, authors own investigation. Source of information - Ref. 1-5, 7, 11, 12, 16, 17, 22, 38.

Heat-related illness and brain oedema

Incidences of brain damage and death during heat-related illnesses have been known since Biblicaltimes39-56. However, the pathophysiology of cellinjury and brain oedema formation in hyperthermiaor related heat-illnesses is still not well known.

Clinical hyperthermia induces brain oedema:Neuropathological observations of heat-relatedillnesses in humans are very limited52,57-59 (Table III).A few sporadic case reports using Cresyl violetstaining on paraffin sections at light microscopy insome brain regions have been described about 50 to60 yr ago52,57. The victims of heat stroke who died at


Table III. Effect of heat on central nervous system damage in clinical cases

Duration of Brain regions Cell damageheat illness

Nerve cells Glial cells Myelin

11 h Cerebral cortex oedema not known not knowncongestiondisintegration

18 h shrunkenhyperchromaticneurons

276 h degeneration proliferationof microgliaand astrocytes

4 d haemorrhagesin white matter

5 h Cerebellum Purkinje cells swollen, proliferation ofdisintegrated oligodendrocytes

5.5 h oedema, swollenand loss of Purkinje cells

72 h Purkinje cells glial proliferationcompletely disappeared

276 h loss of Purkinje Cells glial proliferationgranular cell layerdegeneration of Purkinje phagocytosis bycells glial cells

11 h Dentate nucleus hyperchromatic,capillary engorgement

276 h few shrunken neurons extensive gliosis

276 h Thalamus neuronal loss proliferation of glia

4 h Hypothalamus microhaemorrhagesonly in PVN

8 h no significant change



5 h Midbrain microhaemorrhages in thefloor of IV ventricle, PAG,OM

These pathological observations are based on light microscopy using Crersyl violet stain or haemotoxylin and eosin staining. Noimmunohistochemistry was applied and ultrastructural investigations were not done. PAG, periaqeductal gray matter; PVN,paraventricular nucleus; OM, occulomotor nucleus; h, hours; d, days. Compiled from Ref. 11, 52

various time intervals ranging from 6 h to severalweeks after heat illness exhibit profound changes inthe cerebral cortex and cerebellum52,57.

In heat-injured victims, brain oedema appears tobe the most prominent feature as evidenced byflattening of convolutions and a cerebellar pressurecone along with softening of the brain tissues seenat post mortem. Oedema of the leptomeninges wasalso prominent in many cases. That oedema wasvisible in several cases is further apparent from theincrease in whole brain weight by several hundredgrams52. However, very little emphasis was givenabout the significance of brain oedema in underlyingcell damage by the authors at that time52,57.

These observations clearly suggest that oedemais one of the important factors in inducing thermalbrain damage and induced death in victims of heatrelated illnesses. This idea is further strengthenedby the histological findings showing swollen nervecells and their dendrites in several parts of thecerebral cortex. Many nerve cells contain pyknoticnucleoli and the chromatolysis of cytoplasm andvacuolation is quite common52,60. In the cerebellum,oedema of the Purkinje cell layer was most markedand the number of Purkinje cells was considerablyreduced. Interestingly, the molecular and granularlayers of the cerebellum were not affected. Thedentate nucleus was the most sensitive structureof the cerebel lum, which showed signs ofdegeneration of nerve cells and hyperchromaticreactions52.

The glial cell proliferation and activation ofmicroglia is evident in the cerebral cortex of heat-injured victims. These changes were most prominentin the upper layers of the cerebral cortex comparedto the lower layers. However, damage of the whitematter and signs of demyelination or vesiculation ofmyelin were not detected. Glial cell reactions weremore prominent in the Bergmann layer followed bythe molecular layer11.

In the hypothalamus, a mild to moderate degreeof oedema can be seen in some hypothalamic nuclei.A mild loss of neurons and a slight increase in thenumber of glial cells were also evident. No distinct

cell changes or oedema were seen in the brain stemor in other parts of the brain.

Microhaemorrhage in leptomeninges largelyconfined to the perivascular space were commonduring heat injury. The most pronouncedhaemorrhage was seen in the paraventricular nucleus,the supraoptic nucleus, medial parts of theventromedial and dorsomedial hypothalamic nucleiand less frequently in the perifornical and septalregions and the medial portion of the thalamus.Haemorrhages of the pons and medulla oblongatawere largely confined to the floor of the fourthventricle and/or near the dorsal efferent nucleus ofthe vagus.

Mechanisms of heat induced brain damage:Microhaemorrhages in the brain could be largelyresponsible for the disturbed brain function, e.g.,hemiplegia in the heat-injured victims. It may be thatclot formation due to thrombocytopaenia isaggravated in hyperthermia, which together withmicrohaemorrhages in vital organs leads todeath46,61,62.

Earlier it was believed that brain oedema and cellchanges in heat-injured victims were due topostmortem artefact. However, mild to moderatedegree of nerve cell damage with varying intensityof hyperthermia together with extensive cell loss andproliferation of glia cells rule out the possibility ofpost-mortem artefacts. Malamud et al52 also believedthat the nerve cell changes were real and could bedue to hyperthermia. Therefore, haemorrhages,congestion and oedema could be related to secondaryphenomenon of “heat shock”.

However, oedema, congestion, haemorrhages andnerve cell changes were not consistent with thedegree of hyperthermia in these human cases. Thus,it was believed that the magnitude of brain damagecould be related to many other peripheral changes,such as cardiac or renal failure, alterations in bloodparameters and/or severity of hypotension11. At thattime the concept of neurotransmitter relatedbreakdown of the BBB permeability and braindamage was not well known. Thus, the concept ofhyperthermia induced brain damage in humans in


relation to BBB breakdown requires furtherinvestigation using recently availableimmunocytochemical tools and techniques.

Brain oedema following local hyperthermia

Apart from heat-related illnesses, hyperthermiais quite common following other clinical conditions,such as fever caused by bacterial or viral infectionand cancer therapy63-65. Regional or local heating isthus employed to kill cancer cells66. Local increasein tissue temperature is one of the primary causes ofabnormal cell reaction in the brain during heatexposure.

Very little is known about the effect of localhyperthermia on the human CNS. In patients, anantenna temperature of up to 45°C placed on tumoursdid not result in brain damage. However, heating ofperitumoral brain regions showed cell injury67. Whenthe tumour tissue was heated up to 44-49°C,aggravation of peritumoral oedema and a focal brainswelling was observed68. In contrast to this study,deep brain heating in many patients did not result inheat neurotoxicity69.

Experimental evidences show that local orregional brain heating is associated with oedemaformation, haemorrhages, necrosis, inflammation,gliosis and neuronal damage 65. In these experiments,lethality after hyperthermic insults to the brain is verycommon (Table V). There are reasons to believe thathyperthermia per se can induce such lethalityalthough, this issue is still controversial.

Local heating of dog brain tissue at 43-44°C for30 min results in oedematous swelling 1 wk afterthe heat treatment around the perifocal exposurezone63,70-72. On the other hand, microwave heating ofcat brain at 45°C for 30 min exhibited severalthermally damaged nerve cells 56 days after theprimary insult. Heating of cat brain at 42° C for 50min resulted in extensive coagulation, necrosis andpyknosis of nerve cells in the gray matter, oedemaand vacuolation in the white matter as well aspolymorphonuclear leukocyte infiltration within 3days. Since no lethality was observed in these catexperiments up to 56 days after heat treatment, it is

concluded that heating of small volume of the braindo not alter other vital functions73-75.

Interestingly, histopathological data on localheating of the rodent brain are still not available65.Non-invasive electromagnetic heating of rabbitwhole brain at 42-43°C for 60 min did not result inhistopathological damage or clinical symptoms.However, all animals died within minutes when thebrain temperature was raised to 45°C. Heating of ratspinal cord by a double ring applicator placed on acervical part of the vertebral column usingmicrowave energy at 42.9°C for 38 min resulted inparalysis and neuronal degeneration, myelin damageand microhaemorrhagic foci in the white and greymatters within 4 h65.

Heating of mouse spinal cord at the thoracolumberregion using a water bath (42-43°C) for 80-160 minresulted in paralysis of animals associated with neuronalinjury, demyelination and vascular damage76-78.

Since most of the experiments were conductedunder anaesthetisa, it appears that the passive heatingof the brain may be an entirely different phenomenonrather than the stress associated with heating in theconscious state. Moreover, several anaesthetics,e.g., pentobarbital and ketamine are knownneuroprotective agents79. Thus, further studies areneeded to ascertain the effects of anaesthetics onbrain dysfunction in hyperthermia.

Brain hyperthermia

In most mammalian species, the whole brainoccupies only 2 per cent of the total body mass.However, its energy requirements is estimated to bearound 20 per cent of the total consumption in termof oxygen utilization80-83. The energy needed forneuronal metabolism is transformed into heat asintense heat production is the necessity for the brainmetabolic activity82.

Under resting conditions, the heat production bybrain is utilized properly resulting in normal brainactivity. However, under situations of stress,hyperthermia, and diseases processes, the generationof heat production by the brain and its consumption


in neuronal metabolic activity is impaired leading toabnormal changes in regional brain temperature. Analtered brain temperature is thus responsible forimpaired neuronal activity and may lead to braindysfunction82,83.

A fluctuation in brain temperature within 4°C maybe considered as normal physiological response83.However, further investigations are needed to findout the precise limit and the consequences ofincreased brain temperature responsible for brainpathophysiology. It is still unknown whether increasein brain temperature will have similar cellular andmolecular consequences in a healthy or in thediseased brain. In several cases of brain pathology,both peripheral and central thermoregulatorymechanisms are often impaired.

Regional brain temperatures and thermal gradient:The brain temperature was measured for the first timeby a German physiologist Mortitz Schiff about150 yr ago in awake dogs (see Schiff 1870, cited byJames 1892)84. In this experiment, brain temperaturewas increased by about 1°C in the hungry dog afterpresentation of a meat loaf83. This observationfollowed by later recording of indirect braintemperature from human scalp formed the basis ofthe hypothesis that local heat production in the brainis associated with the mental activity andconsequently psychic function83,84.

Recently, Kiyatkin83 showed that braintemperature varies in different regions (within 0.5to 1.5°C, Table IV). The regional brain temperatureis significantly influenced by external environment,such as changes in ambient temperature, and duringnormal physiological conditions, such as sexualfunction and other motivated behaviours83.

In general, the dorsal brain structures arecomparatively cooler than the more ventrally locatedregions (Table IV), although the reasons behind thistemperature difference are still unclear. This dorso-ventral temperature gradient exists in mostmammalian species including humans84-87. There arereasons to believe that in “cold” brain regions, mostneurons are quiet at rest whereas, in the “warm” brainregions, the majority of neurons are very activeduring normal resting states88,89. However, furtherstudies are needed to clarify these issues.

Fluctuations in brain temperature: Almost allphysiological stimuli induce rapid, specific and long-lasting alterations in the regional brain and thearterial blood temperatures83. The changes in braintemperature in each different areas are faster andgreater than the changes in arterial bloodtemperature83. In general, some stressful stimuli, suchas cage transfer resulted in strongest effect on thebrain temperatures compared to the moderateinfluences caused by social interaction or tail pinch83.


Table IV. Basal brain mean temperature (°C) in the rat brain

Brain regions 23°C 29° C Anaesthesia 38° C#

Cortex 36.56 42.3#

Striatum ventralis 37.57

Striatum dorsalis 36.58

Cerebellum 37.34

Nucleus accumbens 37.26 36.82

Hippocampus 35.58 36.39 29.5 (Urethane) – 6.0° 40.5#

Hypothalamus 37.34 33.0 (Pentobarbital) – 4.5°

Mid brain 37.30 40.5#

Core body 37.4 – 6.0°

Arterial blood 36.62 – 4.5°

Data compiled from Ref. 83; #Sharma HS (unpublished observations)

Exposure to sound resulted in only minimal changesin the brain temperature.

These changes in brain temperature have somestructure specificity. The striatal temperature changesare fast compared to the cerebellum that shows a longdelay and prolonged changes following variousstimuli83. The increase in brain temperature followingelevation of ambient temperature, i.e., 23 to 29°C ismore stable and prolonged compared to otherstressors. However, repeated exposure to highenvironmental temperature gradually showed adecrease in brain temperature response indicatingsome physiological adaptive response90.

Taken together, these observations show thatchanges in external or internal environment influencespecific alterations in brain temperature. Thefunctional significance of such changes is not wellunderstood and requires further investigation.

Brain vs. peripheral hyperthermia: The braintemperature in humans always remains higher thanthat of body or blood temperature91. Thus, thecerebral cortex temperature is 0.2 to 0.8°C higherthan the rectal temperature and about 1.0°C higherthan the jugular venous blood temperature92.Interestingly, during hyperthermia, the venous bloodtemperature correlates more strongly with the coretemperature rather than the brain temperature. Thisindicates that the human brain is vulnerable toadditional thermal load leading to abnormal brainfunction83,121. However, during intense exercise, brainhyperthermia (about 39.5°C) in humans is notnormally associated with fatigue. On the other hand,in rats hyperthermia induced fatigue could be seenwhen the hypothalamic temperature reaches around40.1 to 42.1°C compared to body temperature (40.0to 40.7°C). This indicates that hypothalamus cantolerate larger increase in brain temperaturecompared to the core body temperature. However, itis likely that such a high increase in deep brainstructures is associated with breakdown of the BBB,development of brain oedema and marked damageto the nerve cells83, 91. Thus, excessively high increasein brain temperature appears to contribute toirreversible cell damage leading to long-term mentaldisturbances and/or neurodegeneration.

Influence of anaesthetics on brain temperature:There are reasons to believe that severalanaesthetics wil l influence brain function byinducing changes in regional brain temperature83

(Table IV). General anaesthesia induced bypentobarbital (50 mg/kg, i.p.) reduces hypothalamictemperature by 4.5°C whereas the body temperatureis decreased only by 3.5°C83. Administration ofurethane (1.5 g/kg, i.p.) results in lowering ofhippocampal tenerature by 6° C whereas, the bodytemperature declines by only 4°C93. This indicatesthat anaesthetics are able to decrease braintemperature more than the body temperature.

Interestingly, body warming during anaesthesiaresults in maintaining of the core temperature only.The brain temperature increased only slightly duringwarming probably because of anaesthesia inducedmetabolic inhibition83. Similar effect on brainhypothermia in mammals is seen during chloralose,chloral hydrate and halothona anaesthesia94,95.

These observations suggest that anaesthetics mayexert some neuroprotective effects duringhyperthermia by lowering the brain temperature.However, this is a feature that requires additionalinvestigation.

Brain hyperthermia induced by drugs of abuse: Alldrugs of abuse and psychostimulants includingopioids increase whole body oxygen consumptionand heat production96. Thus, morphine, cocaine,heroin, amphetamine derivatives and cannabinoidsinduce profound hyperthermia97-100.

Although, increase in body temperature is quitecommon following consumption of these drugs,their effect on brain temperature is not very wellknown. Kiyatkin83 showed that administration ofcocaine increased brain temperature (1.2°C) innucleus accumbens and in hippocampusremarkably. However, the brain hyperthermia wasnot correlated with the activation of locomotorbehaviour. On the other hand, a robust increase inbrain temperature was seen (3.4°C) followingadministration of amphetamine derivatives. Thiseffect of the drugs on brain temperature was muchmore aggravated when administered at 29°C


environmental temperature compared to 23°C101.This indicates that the magnitude of drugs inducedbrain hyperthermia is increased during warmenvironment probably due to a combination ofdrug-induced heat production and impairment ofheat dissipation83.

There are reasons to believe that drug inducedbrain hyperthermia is largely responsible forneurotoxicity commonly seen with these drugs ofabuse102,103. Thus, it would be interesting to examineBBB dysfunction and brain oedema following drug-induced hyperthermia to further confirm thishypothesis. Preliminary observations from ourlaboratory show that morphine andmethamphetamine administration in rodents isassociated with profound BBB disruption to

endogenous serum proteins (unpublishedobservations).

Whole body hyperthermia induces brain oedema

Whole body hyperthermia (WBH) is commonlyused as therapy for tumour patients66. However,heating of all the tissues including CNS will resultin adverse effects65 (Table V).

Exposure of dogs to 60°C hot air in a cabin for2 h did not result in brain oedema formation measuredusing alterations in epidural pressure recordings.Based on this observation, the authors concluded thatexposure of animals to WBH does not induce brainoedema104. However, when dogs were exposed tomicrowave heating with 106.5 MHz for 60 min, their


Table V. Effect of heat on the CNS damage in the laboratory animals

Species Exposure Tissue Duration Pathologicaltemp (°C) exposed (min) findings

Dog 42-46e cerebral hemisphere 30 Oedema, haemorrhages

42-43.5a occipital cortex 50-70 gray and white matterdamage

43-44a cerebral hemisphere 30 necrosis, inflammation

40-44a frontal cortex 30 necrosis, gliosis,cerebral hemisphere fibrosis

Cat 45a forebrain 30 no change

42-48c occipital cortex 50 gray and white matterdamage

41-48c occipital cortex 50 necrosis, inflammation

Mouse 42d spinal cord 60 not known

41.2-45.2b spinal cord 60 not known

42-43.5d spinal cord 20-100 neuronal and vasculardamage,demyelination

Rat 41.2-43.2a spinal cord 30-120 neuronal damage,white matter necrosis,gliosis

43.4-46b spinal cord 15-30 not knwon

42.6-43.8a spinal cord 60 not known

Rabbit 42-43b whole brain 60 no change

45b few not known

These observations are based on very crude pathological examination done from 4-24 h, 3,7,14 and 28 days after thermal insults. Insome cases details of pathological examination are not available. a, Microwave; b, radiofrequency; c, ultrasound; d, water bath;e, warm blood infusion. Source of data - Ref. 11, 65.

lumbar spinal canal temperature reached between42.5 to 43°C. In these animals, severe haemorrhageand oedema in the lumber spinal cord and pelvic limbdysfunction was seen 12-24 h after hyperthermia104.It is interesting to note that in all these investigationsthe state of the BBB, CBF or oedema was notexamined. Thus the impact of hyperthermia on theseimportant aspects of brain dysfunction is still lacking.

Brain hyperthermia affects neural function: Thereare reasons to believe that alteration in braintemperature influences neuronal activity105. This isevident from the fact that neuronal function isprimarily dependent on bioelectrical activity andneurochemical transmission that are related tometabolic heat production83. Thus, any alteration inbrain temperature is likely to affect neuronalfunction.

Experimental evidences suggest that hyperthermiawithin the physiological range (<38°C) do not altermembrane potential but decrease Ca2+-dependenthyperpolarization83. This will result in a decrease ininter-spike interval and an increase in the dischargerate106,107. However, till date studies on neuronalfunction in hyperthermic range (>38 to 40°C) are stilllacking and require further investigation108.

Recently, a subgroup of transient receptorpotential (TRP) subfamily of cation channels that arevery sensitive to hyperthermia, has been identifiedin the primary afferent neurons of dorsal root andtrigeminal ganglia109,110. Some of these receptors arealso expressed in brain tissues, however, their rolein temperature sensitivity is still unclear.

Increase in brain temperature enhancesneurotransmitter release causing alterations inreceptor mediated events leading to neural and non-neural dysfunction83. There are indications thatincreased release of neurochemicals during brainhyperthermia could be compensated by rapid re-uptake of these neurotransmitters83. However,carefully controlled additional investigations arenecessary to further clarify these points.

Hyperthermia caused by fever is supposed to bean adaptive response in the organisms. However,

pathological hyperthermia in such situations (>42°C)may induce abnormal brain function111,112. Thus,hyperthermia up to certain limits may influencerelease of neurochemicals and alter membrane and/or synaptic functions. An abrupt and robust increasein neuronal or regional brain temperature maydirectly induce cell damage and/or cell death83. Thisis evident from the fact that when the incubationtemperature of cultured bovine endothelial cells israised from 37 to 41° C, only 9 per cent cellssurvived. However, when the incubation temperatureis increased further to 43°C, only 0.2 per cent cellsremained viable113.

Since brain cells (both neuronal and non neuralcells, such as glial and endothelial cells) are mostsensit ive to hyperthermia compared to otherorgans114, i t appears that increase in braintemperature will adversely affect the neuronal andnon neuronal cell functions. It is still unknownwhether hyperthermia per se inf luencesneurotoxic i ty or through some indirectmechanisms, e.g., via release of neurochemicals,cytokines and other cel lu lar and molecularfactors111,115. This is a subject that is currently beinginvestigated in our laboratory using in vivo rodentmodels.

It has been established that brain hyperthermiacaused by local or systemic heating is associatedwith expression of heat shock proteins116-118. Largebody of evidences suggests that induction of heatshock protein (HSP) following brain hyperthermiais associated with neuroprotection or cellularadaptation to heat induced adverse effects111,112,119.However, the magnitude and intensity of HSPinduction appears to play important roles in cellinjury or cell protection. It appears that mildhyperthermia induced moderate elevation of HSPin the CNS and resulted in cell survival or recovery,probably by increasing the cellular resistance todamage. On the other hand, massive upregulationof HSP during severe hyperthermia induces celldeath via apoptotic pathways causing DNAdamage120. Further studies on the consequences ofbrain hyperthermia induced alteration in cellularevents using recently available cel lular andmolecular tools are needed.


Our investigations on WBH and brain oedemaformation

Studies carried out in our laboratory during thelast three decades show that the CNS ishighly vulnerable following WBH of consciousrats10,11,17-21, 66, 121-135. It appears that WBH influencesbrain function by modifying the BBBpermeability17,19,66,123,126. An increased permeability ofthe BBB is responsible for vasogenic oedemaformation and cell injury21,124,125,129-131.

The rat model of WBH: We developed a model ofWBH in which animals develop symptoms of heatillness without heat stroke18-20,17,121,123. The modelconsists of exposing the rats to WBH at 38°C in abiological oxygen demand (BOD) incubator for 4 h(Table VI). The relative humidity (45-50%) and windvelocity (20- 25 cm/sec) was kept constant17.

At the end of 4 h WBH at 38°C, some rats layprostrate in cages and did not move even after gentlepushing although the righting reflex was not lost17,121.A few rats (<20%) whose body temperature exceeded42°C, died either during or a few minutes aftertermination of WBH10,17. These observations suggestthat the model can be used to study brain pathologyin heat stress and to explore new therapeuticstrategies to treat heat-related illnesses.

WBH induces breakdown of the BBB: In order toexamine the breakdown of the BBB in relation to

vasogenic oedema formation in heat stress, we usedtwo exogenous protein tracers, i.e., Evans blue (0.3ml of a 2 % solution, pH 7.4) and radioactive iodine[131]I-sodium (100 µCi/kg)17,18. These tracers bind toserum albumin when injected into the circulation andthus their leakage into the brain representextravasation of tracer-protein complex17,26,27.

Exposure of rats to 34 or 36°C did not result inbreakdown of the BBB permeability17,121,123. However,rats exposed to 4 h WBH at 38°C exhibited profoundextravasation of Evans blue and radioactive iodine,a feature not seen at the end of 1 or 2 h heat exposure.This indicates that exposure temperature and durationof WBH are important factors in determining leakageof BBB to protein tracers. Whether the permeabilityof the BBB to small molecular tracers was open atearlier periods following WBH is not known andrequire additional investigation.

The BBB breakdown was seen in selective areasof the brain indicating specific thermal sensitivity tosome brain regions depending on the size of tracersused (Figs. 1 and 2). Thus, Evans blue staining (MW68 000 kD) was most prominent in the cingulatecortex (99%), followed by occipital cortex (96%),parietal cortex (94%), cerebellum (90%), temporalcortex (88%), frontal cortex (85%), hypothalamus(78%) and thalamus (64%). Whereas, a significantincrease in radioiodine (MW 32000 kD) was apparentalso in hippocampus, caudate nucleus, superiorcolliculus, inferior colliculus, pons and medulla


Table VI. Stress symptoms in control and heat stressed rats

Parameters examined Control Heat stress at 38° C in BOD chamber

1 h 2 h 4 h(n = 8) (n = 6) (n = 8) (n = 12)

A. Stress symptoms

Rectal temperature (°C) 37.42±0.23 38.41±0.32 39.24±0.21 41.48±0.23

Salivation nil ++ +++ ++++

Prostration nil nil nil ++++

Gastric haemorrhage nil 4 ± 3 8 ± 3 34 ± 8

(microhaemorrhages)

Control rats kept in room temperature (21±1°C); Rats exposed in a biological oxygen demand (BOD) incubator at 38°C for heatstress; nil = absent; ++, mild; +++, moderate; ++++, severe. Source: Ref. 10, 11, 17


Fig. 1. Hyperthermia associated with 4 h heat stress (a) and breakdown of the blood-brain barrier (BBB) permeability (b) to proteintracers, Evans blue and radioiodine. A direct effect of hyperthermia on BBB disruption is unlikely as several drug treatments preventedthe BBB leakage without attenuating hyperthermia. This indicates that heat-induced secondary changes in the brain are responsiblefor BBB breakdown. Reprinted with permission from Ref. 122.

Fig. 2. Effect of multiple opioid receptor antagonists (naloxone and naltrexone) and an L-type Ca2+ channel blocker (nimodipine)on heat stress induced alterations in the rectal temperature (a) and BBB permeability (b) following 4 h heat stress (HS). Increasedbrain water content (c) and volume swelling of brain (% ƒ, d) closely corresponds to the BBB permeability changes in heat stress.Values are mean±SD from 6 to 8 rats. * P = < 0.05; ** = P < 0.01; ANOVA followed by Dunnet’s test for multiple group comparisonfrom one control. Reprinted with permission from Ref. 122.

(Sharma 2004). A widespread distribution ofradiotracer compared to Evans blue dye may be dueto differences in protein binding capacity of theformer tracer or due to differences in proteins towhich these tracers adhere into the circulation121,123.

WBH induces brain oedema: Extravasation ofproteins in cerebral compartment alters osmoticgradients across the endothelial cell membraneresulting in water transport from the vascularcompartment to the brain extracellular space1,7,26.Thus, breakdown of the BBB permeability to proteintracers following WBH will result in vasogenic brainoedema formation10.

To test this hypothesis, we examined changes inthe brain water content and volume swelling in ratssubjected to 4 h WBH at 38°C21,124. The brain watercontent was measured in each animal using thedifferences in wet and dry weight of the brain14,15.

The percentage volume swelling (% f) wasdetermined from the changes in brain water contentbetween control and heat stressed animals using theformula of Elliott and Jasper136. In general, anincrease of 1 per cent water content will reflect about3 per cent increase in volume swelling1,21,26,124,125.

Our result supports the idea that the brain oedemaformation following WBH is closely associated withbreakdown of the BBB (Fig. 2). Thus, profoundincrease in brain water content and volume swellingwas observed in rats subjected to 4 h WBH10, whereasshort duration of heat exposure did not induce brainoedema formation10,11.

WBH, brain oedema and death: At the end of 4 h WBHat 38°C, few animals whose body temperatureexceeded 42°C died shortly after the heat exposure10,17.Postmortem studies in these animals exhibited fluidityof all the cerebral components indicating massive


Fig. 3. Representative examples of light microscopic changes in the brain of rats following 4 h heat stress (HS). Degeneration(arrowheads) of nerve cells in the dentate gyrus and in the CA-4 region (*) of the hippocampus is clearly visible heat stress (HS, b)compared to the control (Cont, a). Several damaged and distorted nerve cells in the brain stem regions following HS is apparent(d, arrows) compared to control (c). Bars: a,b = 50 µm; c,d = 20 µm. Reprinted with permission from Ref. 122.

volume swelling of the brain10. Measurement of brainwater showed an extensive increase compared to thoserats who survived10,17,138. These observations suggestthat the magnitude and severity of brain swelling inthe closed cranial compartment is responsible for heat-induced deaths10,139.

WBH and regional brain oedema: In order to findout a regional difference in brain oedema formation,we examined regional changes in the brain watercontent following WBH10,11. A significant differencein regional brain water was observed. Increase in thebrain water content was highest in the hippocampusand the brain stem (5%) followed by cerebellum (4%)and cerebral cortex (3%). These observations suggestthat WBH has the capacity to induce a selectiveincrease in the regional brain water content indicatinga selective vulnerability of brain regions by heat, asubject that require further investigation.

Brain pathology in WBH

Alterations in the BBB permeability and leakageof plasma proteins in brain compartments followingWBH alter ionic, chemical and immunologicmicroenvironment leading to neuronal, glial andmyelin reactions and development of brainpathology.

Neuronal changes: Nissl staining showed severaldark and distorted neurons in oedematous regions ofthe cerebral cortex, brain stem, cerebellum, thalamusand hypothalamus along with severe loss of nervecells (Fig. 3)127,128. In the hippocampus markedneuronal damage is evident in the CA-4 subfield(Fig. 3) although oedematous cells and generalsponginess were present in the wholehippocampus132,133.


Fig. 4. Representative example of neuronal changes following heat stress in young (HSY) rats compared to controls (Cont). Increasedexpression of glial fibrillary acidic protein (GFAP, a,b, blank arrow) and a considerable decrease in the myelin basic protein (MBP,c,d, arrows) immunoreactivities are apparent in heat stressed rat compared to the controls. A decrease in MBP expression reflectsdamage and degeneration of myelin (d*). Bars: a,b = 25 µm; c,d = 50 µm. Reprinted with permission from Ref. 122.

At the ultrastructural level, several nerve cellsshowed degenerated nucleus accompanied witheccentric nucleolus in the cerebral cortex,hippocampus, cerebellum, thalamus, hypothalamus,and brain stem (Fig. 4). In some nerve cells thenucleolus is attached to one end of the nuclearmembrane and the nuclear membrane exhibit manyirregular folding. Several nerve cells in general aredark in appearance containing vacuolated cytoplasmindicating neurodegeneration in WBH.

Synaptic damage: Swollen synapses with damage toboth pre- and post-synaptic membranes are quitecommon in thalamus, brain stem, hypothalamus,cerebellum, hippocampus and in cerebral cortexfollowing WBH (Fig. 4). This indicates that WBH is

capable to influence neurotransmission in the CNS,a feature that requires further investigation.

Glial changes: Profound upregulation of glial fibrillaryacidic protein (GFAP) is seen in the brain stem,cerebellum, thalamus and hypothalamus. The cerebralcortex and hippocampus showed only a mild increasein the GFAP activity after WBH129 (Fig. 4). Thisindicates a regional difference in the susceptibility ofneuron versus glial responses in WBH, a new subjectthat require further detailed investigation.

Myelin changes: Using myelin basic protein (MBP)immunostaining, vesiculation or degradation ofmyelin is commonly seen following WBH. At theultrastructural level vesiculation of myelin and


Fig. 5. Ultrastructural changes in the rat’s brain following 4 h heat stress (HS). In the cerebral cortex, one nerve cell with dark andelectron dense cytoplasm (arrows) is seen following HS (a) along with other degenerative changes in the neuropil (b, c, d). Highpower electron micrograph from the parietal cerebral cortex cellular layer III showing damaged synapses (arrows), vesiculation ofmyelin and membrane damage following HS (b). A completely collapsed microvessel (arrowheads) and distorted granule cells in thecerebellum are seen following HS (c). Perivascular oedema (*), membrane damage and leakage of lanthanum across the microvessels(d) are quite frequent in HS. Bars: a = 0.6 µm; b = 0.1 µm; c,d = 1 µm. Reprinted with permission from Ref. 122.

swollen axons are common findings (Fig. 4). Manyunmyelinated axons are also swollen (Fig. 5). Thus,a decrease in MBP immunostaining was mostpronounced in the brain stem reticular formation,pons and medulla11,121. Damage of myelin isassociated with profound neurological symptoms and

alterations in various motor or sensory functions.Thus, further studies are needed to find out specificpathways of myelin damage in the CNS in WBH.

Pharmacological manipulations of brain oedemain WBH

That breakdown of the BBB is associatedwith vasogenic oedema formation, and cell damagewas further confirmed in WBH using apharmacological approach (Figs 1 & 2).Interestingly, the drugs that prevented the BBBpermeability following WBH are also able tothwart the brain oedema formation(Table VII)10,121,122,126,139. A strong correlat ion(r = 0.97, P<0.001) was observed betweenextravasation of protein tracers and brain oedemaformation in WBH (Fig. 6). These observationsprovide strong evidences that the breakdown of theBBB is associated with vasogenic brain oedemaformation in WBH. Interestingly, oedema and cellchanges at the ultrastructural level are alsoconsiderably reduced in drug animals by drugs thatare able to attenuate BBB disruption (Fig. 7).


Fig. 6. Correlation of BBB disruption (radioiodine %) and brain oedema formation (increased brain water content %) in heat stressin control, untreated and various drug-treated rats. A strong correlation between BBB breakdown and oedema formation is apparent(P <0.001). Reprinted with permission from Ref. 122.

Table VII. Effect of drugs on BBB and brain oedema in 4 h

heat stress. All drugs were administered before the onset of heat

stress

Drug BBB Brain oedema

Untreated ++++ ++++

p-CPA - -

indomethacin - -

diazepam - -

Cyproheptadine +++++ +++++

vinblastine -/+ -/+

Phenoxynbenzamine +++++ ++++++

Propranolol +++ +++

-, absent; +, weak; +++, mild; ++++, moderate; +++++, severe

Source: Ref. 10, 11, 17, 18

BBB, Blood brain barrier

-2.5 0 2.5 5 7.5 10 12.5 15 17.5 20 22.5

Oedema%Y = -15.106 + 30.012 * ×; R2 or r = 0.968

Possible mechanisms of BBB dysfunction andbrain oedema formation in WBH

Our pharmacological studies clearly point out thatbreakdown of the BBB permeability either directly orthrough some indirect mechanisms123,134-136 isresponsible for brain oedema formation. We usedseveral pharmacological agents to influnce BBBbreakdown and oedema formation in WBH (Figs 1 &2). Thus, drugs influencing serotonin, prostaglandin,opioids are able to reduce brain oedema formationprobably by attenuating BBB disruption in WBH124.

The cerebral capil lary walls containprostaglandin, cAMP and cGMP synthesis andcatabolizing enzymes29,140,141. A transientaccumulation of either prostaglandins, cAMP orcGMP in cerebral microvessels leads to an increasein vesicular transport of tracer substances124,142. It

seems quite likely that release of neurochemicalsfollowing hyperthermia stimulates nitric oxide (NO)production either directly or through cytokinemediated action in the brain124. Increased productionof NO causes breakdown of the BBB permeabilitythrough cGMP mediated mechanisms124. Increasedprostaglandin, NO or histamine biosynthesis incerebral microvessels stimulates cAMP and/or cGMPsynthesis143. The increased cAMP or cGMP levelstimulates vesicular transport causing breakdown ofthe BBB permeability29 (Fig. 8).

Leakage of plasma proteins across the microvesselsfollowing BBB disruption is an important factorcontributing to vasogenic brain oedema formation andcell injury (Fig. 8). This hypothesis is in line with theresults showing the drugs which prevented the BBBpermeability following heat stress, were able tosignificantly thwart the brain oedema formation11.


Fig. 7. Drugs that attenuated BBB disruption in heat stress is also able to reduce oedema formation and cell injury at the ultrastructurallevel. Thus, cell changes and oedema formation are considerably reduced by pretreatment with indomethacin (a), p-CPA (d), naltrexone(e) or nimodipine (f) compared to untreated 4 h heat stressed (HS, c) rat. Pretreatment with cyproheptadine that did not reduce theBBB breakdown is unable to reduce oedema formation and cell injury (b). bars: a,d = 1 µm; b,c,e,f = 0.5 µm. Reprinted withpermission from Ref. 122.

Conclusion

Based on the above facts, it appears that WBHinduces brain oedema probably due to alteration inthe BBB function to proteins. This breakdown of theBBB appears to be mediated through specificneurotransmitter receptors induced signaltransduction pathways. Hyperthermic insults to CNSinduce profound cellular stress associated withrelease of several neurochemicals, lipid peroxidationand generation of free radicals133-135,144,145. Cellularstress and alterations in neurochemicals may triggerfree radical generation and opening of cationpermeable channels leading to an increasedaccumulation of intracellular Ca2+ in the brainmicroenvironment146-150. The intracellular Ca2+ bindsto calmodulin, a co-factor of nitric oxide synthase(NOS) and may stimulates NO production150-154. TheNO binds to the heme-iron protein in guanylylcyclase to elicit cGMP formation that contributes tomicrovascular permeability disturbances155-159(Fig. 8).

Breakdown of the BBB permeability will thusallow many serum factors or other vasoactive

compounds to enter into the CNScompartments17,27,124. Profound alterations inextracellular fluid microenvironment of the cellularcompartments in the brain by ionic, chemical,immunological and metabolic reactions will induceto vasogenic oedema formation and contribute to thenerve cells, glial cells or axonal injury17,27,66,121,122.Thus, brain oedema formation in WBH could be oneof the instrumental causes in underlying brain celland tissue injury. Further studies are needed toattenuate brain oedema formation in heat-relatedillnesses probably through modifying BBB function,a feature currently being examined in our laboratory.

Acknowledgment

This work was supported by grants from Swedish MedicalResearch Council; Göran Gustafsson Foundation, Sweden, AstraHässle, Mölndal, Sweden; Alexander Humboldt Foundation,Bonn, Germany; The University Grants Commission, NewDelhi; Indian Council of Medical Research, New Delhi, India.Secretarial assistance of Mrs. Aruna Sharma is highlyappreciated.

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Reprint requests: Prof. Hari Shanker Sharma, Laboratory of Cerebrovascular Research, Department of Surgical SciencesAnaesthesiology & Intensive Care Medicine, University Hospital, Uppsala University, S-751 85 Uppsala, Swedene-mail: [email protected]


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